Abstract Alzheimer's disease (AD) is a chronic neurodegenerative disease that causes 60% to 70% of cases of dementia and is the 6th leading cause of death in the United States. AD usually manifests in individuals over 65 years old and the incidence increases with age. Currently, there are five FDA-approved Alzheimer's drugs that only provide temporary symptomatic relief but do not prevent or delay the disease progression. Thus, developing effective therapies of AD represent an urgent medical need. Although the etiology of AD remains elusive, aging is the greatest known risk factor. As such, strategies that improve healthy aging may serve as effective means for AD management. In this proposal, we will interrogate this idea by focusing on a naturally occurring lipid molecule, oleoylethanolamide (OEA), that we recently identified to improve lifespan and healthspan in Caenorahbditis elegans. Importantly, OEA and its signaling pathways are highly conserved from worm to mammals, including humans, and OEA has been shown to regulate feeding and body weight and inhibit high-fat diet induced obesity and metabolic dysfunctions in rodents. Our proposal is supported by strong scientific premise because alterations in lipid metabolism and storage become prevalent during aging, while midlife obesity and its metabolic comorbidities such as hyperinsulinemia, diabetes, and altered lipid metabolism increase the risk of late-onset AD. Thus, lipid regulators that promote metabolic health and longevity like OEA may be a promising target for the prevention and treatment of AD. This multi-PI application joins force of three individuals with outstanding expertise in aging biology and lipid metabolism (Meng Wang), AD mouse models (Hui Zheng), and medicinal chemistry (Jin Wang), and is built on our ongoing collaborations. Together we will 1) elucidate the effects of OEA in AD C. elegans models and develop and test new and highly potent OEA analogs; 2) determine the therapeutic effect of OEA analogs in AD mouse models; and 3) understand the role of OEA analogs in AD under high metabolic stress conditions. Our proposal is highly innovative as it addresses a new concept to apply pro- longevity compounds for AD therapy through a novel lipid-mediated mechanism. It is also highly significant as it is directly therapeutically relevant and tackles a disease of unmet medical needs.